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| Status |
Public on Dec 27, 2020 |
| Title |
IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice I |
| Organism |
Mus musculus |
| Experiment type |
Other
|
| Summary |
CD4+ and CD8+ T cells can reciprocally differentiate into Th/Tc1, Th/Tc17 and Th/Tc22. Although alloreactive Th/Tc1 cells play a critical role in initiating pathogenesis of gut acute graft-versus-host disease (Gut-aGVHD), the pathogenic T cells in steroid-resistant Gut-aGVHD (SR-Gut-aGVHD) remains unclear. Here, we show that in murine models of SR-Gut-aGVHD, the pathogenesis is associated with reduction of IFN-g+ Th/Tc1 and IL-17A+IL-22- Th/Tc17 but expansion of IL-17-IL-22+ Th/Tc22, particularly Tc22 cells. IL-22 from Th/Tc22 cells causes dysbiosis. Using a Gut-aGVHD model induced by alloreactive IFN-g-/- CD8+ T cells, we show that the Gut-aGVHD pathogenesis requires both dysbiosis and depletion of CX3CR1hi mononuclear phagocytes (MNP) that regulate intestinal bacterial translocation. Absence of IFN-g leads to preferential expansion of Tc22 that induce dysbiosis by augmenting RegIIIg production, and depletion of CX3CR1hi MNP via its PD-1 interaction with tissue PD-L1. Interestingly, SR-Gut-aGVHD is also associated with depletion of CX3CR1hi MNP that reduces expansion of Tc22 under steroid treatment. Our studies indicate that expansion of Th/Tc22, dysbiosis, and depletion of CX3CR1hi MNP cells play critical roles in SR-Gut-aGVHD pathogenesis. These results provide new avenue towards studies in patients and call for caution in clinical testing of IL-22 agonists or IFN-g antagonist in patients.
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| Overall design |
Experiments of the relationship between the SR-Gut-aGVHD pathogenesis and the regulation of IFN-γ+ Th/Tc1, IL-17A+IL-22- Th/Tc17 and IL-17-IL22+Th/Tc22 cells.
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| Contributor(s) |
Song Q, Zeng D |
| Citation(s) |
33547295 |
| |
| Submission date |
Oct 05, 2020 |
| Last update date |
Feb 22, 2021 |
| Contact name |
Defu Zeng |
| E-mail(s) |
dzeng@coh.org
|
| Phone |
626-218-3587
|
| Organization name |
The Beckman Reseach Institute
|
| Department |
Immunology & Theragnostics
|
| Lab |
Defu Zeng Lab
|
| Street address |
1500 East Duarte Road
|
| City |
Duarte |
| State/province |
California |
| ZIP/Postal code |
91010 |
| Country |
USA |
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| Platforms (1) |
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| Samples (27)
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| This SubSeries is part of SuperSeries: |
| GSE159419 |
IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice |
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| Relations |
| BioProject |
PRJNA667450 |
| SRA |
SRP286400 |
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